Poziotinib for EGFR exon 20-insertion NSCLC: Clinical efficacy of the phase 2 ZENITH trial and differential impact of EGFR exon 20 insertion location on sensitivity

作者：Xiuning Le, Jacqulyne Robichaux, Monique B. Nilsson, R. S. K. Vijayan, Ashwin Ravichandran, Jia Wu, Yasir Y. Elamin, Lingzhi Hong, Jun Pei, Jun He, Sonia Patel, Hibiki Udagawa, Sriramvignesh Mani, Chang Woon Jang, Jeffrey M. Clarke, Nishan Tchekmedyian, Jonathan W. Goldman, Mark A. Socinski, Gajanan Bhat, Sharon Leu, Veronica Bunn, Zhenqiang Su, Sylvie Vincent, John W. Lawson, Jason B. Cross, John V. Heymach · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61817-8 · 被引用次数：9 · 研究领域：Lung Cancer Treatments and Mutations、HER2/EGFR in Cancer Research、Colorectal Cancer Treatments and Studies

EGFRex20 insertions (EGFRex20ins) can be classified as near- and far-loop based on the insertion location, however, the impact of location on responses to various EGFR tyrosine kinase inhibitors (TKIs) is poorly understood. In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. Molecular dynamics simulations reveal that near-loop insertions have multiple conformational states and lower transitional energy than far-loop insertions. ZENITH20 trial cohort 1 (NCT03318939) evaluates poziotinib in EGFRex20 NSCLC patients (n = 115) and demonstrates an objective response rate of 14.8% (95% Confidence Interval [CI], 8.9 to 22.6, primary endpoint of the trial). Although the study’s primary efficacy endpoint was not met in the overall cohort, the exploratory analysis indicates poziotinib has superior benefit in EGFRex20 near- versus far-insertions showing greater mean tumor size reduction (−25.9% vs. −9.8%, p = 0.0014) and progression-free survival (PFS, 11.1 vs. 3.5 months, p = 0.016). In comparison, in the previously published EXCLAIM trial (NCT02716116), mobocertinib demonstrates similar activities across both groups in tumor size reduction (−38.5% vs. −34.1%, p = 0.59) and PFS (12.0 vs. 13.0 months, p = 0.99). Therefore, EGFRex20ins location differentially impacts the sensitivity of TKIs. The location of EGFR exon 20 loop insertions (EGFRex20ins) has been show...